Discovery of First-in-Class Peptidomimetic Neurolysin Activators Possessing Enhanced Brain Penetration and Stability

Peptidase
neurolysin (Nln) is an enzyme that functions to cleave
various neuropeptides. Upregulation of Nln after stroke has identified
the enzyme as a critical endogenous cerebroprotective mechanism and
validated target for the treatment of ischemic stroke. Overexpression
of Nln in a mouse model of stroke results in dramatic improvement
of stroke outcomes, while pharmacological inhibition aggravates them.
Activation of Nln has therefore emerged as an intriguing target for
drug discovery efforts for ischemic stroke. Herein, we report the
discovery and hit-to-lead optimization of first-in-class Nln activators
based on histidine-containing dipeptide hits identified from a virtual
screen. Adopting a peptidomimetic approach provided lead compounds
that retain the pharmacophoric histidine moiety and possess single-digit
micromolar potency over 40-fold greater than the hit scaffolds. These
compounds exhibit 5-fold increased brain penetration, significant
selectivity over highly homologous peptidases, greater than 65-fold
increase in mouse brain stability, and ‘drug-like’ fraction
unbound in the brain.